SAT-666 Stanniocalcin-1 as a Key Mediator of Roux-en-Y Gastric Bypass-Induced Amelioration of Metabolic-Associated Steatohepatitis

Abstract Disclosure: J. Oh: None. C. Ku: None. Introduction: Metabolic-associated steatohepatitis (MASH) is a severe form of metabolic dysfunction-associated fatty liver disease (MAFLD) linked to obesity and metabolic syndrome. Roux-en-Y gastric bypass (RYGB), a bariatric surgery for morbid obesity, effectively reduces weight and improves obesity-driven conditions, including liver disease. However, the mechanisms by which RYGB impacts MASH progression remain unclear. This study aims to identify factors mimicking RYGB's effects and develop novel therapeutic strategies for MASH. Method: Wistar rats underwent RYGB surgery, and small intestinal tissues were collected for RNA sequencing to identify differentially expressed genes encoding secreted proteins. Protein expression of selected candidates was validated using ELISA in portal vein plasma. To assess therapeutic potential, a mouse model of MASH was established through a methionine-choline deficient (MCD) diet. Result: After feeding rats with a high-fat diet for 16 weeks, Roux-en-Y gastric bypass (RYGB) surgery was performed. Eight weeks post-surgery, RNA sequencing was conducted on the jejunum (Alimentary limb) and ileum (Common limb). Among these, secreted genes were filtered, and a list of genes secreted into the bloodstream or surrounding tissues was collected. Stanniocalcin-1 (STC-1) was identified as a significantly upregulated gene, showing an 17-fold increment (LogFC). Blood samples from the portal vein of the RYGB group revealed a significant increase in STC-1 protein levels (p<0.05). To evaluate the effect of STC-1 on MASH and fibrosis, inflammation was induced using LPS in the mouse monocyte cell line (Raw264.7) and the human monocyte cell line (THP-1). Treatment with STC-1 significantly reduced the expression of inflammation-related genes, including IL-1β, TNF-α, IL-6, and CCL2. Furthermore, in human hepatic stellate cells (LX-2), fibrosis was induced with TGF-β. STC-1 treatment led to a significant reduction in fibrosis-related genes such as TIMP-1, TGF-β, COL1A1, and ACTA2. In a mouse model of MASH induced by the MCD diet, recombinant STC-1 protein was administered. Liver tissue analysis showed a marked reduction in inflammation and fibrosis. Conclusion: This study demonstrates that STC-1, which is overexpressed in the intestine following RYGB surgery, is secreted into the portal circulation and delivered to the liver, where it ameliorates MASH. These findings highlight a key mechanism underlying the therapeutic effects of RYGB on MASH. Presentation: Saturday, July 12, 2025